PRUNE2 has played an important role in regulating tumor cell differentiation, proliferation and invasiveness in neuroblastoma. Our previous study revealed that the PRUNE2/OBSCN relative expression could distinguish between gastrointestinal stromal tumor and leiomyosarcoma accurately. However, the correlation between PRUNE2 expression and prognosis was poorly understood in leiomyosarcoma patients. In this study, we aim to evaluate the prognostic role of PRUNE2 in leiomyosarcoma. The PRUNE2 protein expression was detected by immunohistochemistry (IHC) in 30 formalin-fixed and paraffin-embedded (FFPE) leiomyosarcoma tissues from MD Anderson Cancer Center (MDACC) and the high expression of PRUNE2 was 36.7% (11/30). To validate the results, another cohort of 45 FFPE leiomyosarcoma tissues from Tianjin Medical University Cancer Institute & Hospital (TMUCIH) was collected and PRUNE2 protein expression was detected by IHC. The results showed that the high expression rate of PRUNE2 protein in TMUCIH samples was 37.8% (17/45) and the elevated PRUNE2 expression was significantly associated with tumor size (P=0.03). Not only the high expression level of PRUNE2 protein was a significant favorable prognostic factor for overall survival in TMUCIH leiomyosarcoma patients (P<0.05), multivariate analysis revealed that the protein expression of PRUNE2 was also an independent prognostic factor. These data suggest that increased PRUNE2 protein expression may serve as a favorable prognostic marker in human leiomyosarcoma.